1. Field of the Invention
This invention relates to neurology, neurobiology and molecular biology. More particularly, this invention relates to methods for promoting myelination and increased neuronal survival and treating demyelination and dysmyelination disease by the administration of a TrkA antagonist. The invention also relates to methods of inhibiting or decreasing Sp35 expression by the use of a TrkA antagonist. Additionally, the invention relates generally to methods for blocking Sp35 and TrkA and inhibiting or decreasing TrkA phosphorylation by the administration of a Sp35 antagonist.
2. Background Art
Nerve cell function is influenced by contact between neurons and other cells in their immediate environment (Rutishauser, et al., 1988, Physiol. Rev. 68:819). These cells include specialized glial cells, oligodendrocytes in the central nervous system (CNS), and Schwann cells in the peripheral nervous system (PNS), which sheathe the neuronal axon with myelin (Lemke, 1992, in An Introduction to Molecular Neurobiology, Z. Hall, Ed., p. 281, Sinauer).
The formation of the myelin sheath is an exquisite and dynamic example of cell-cell interaction that involves the myelin-forming cell and the neuronal axon. It is generally thought that during development axons control whether they will become myelinated by expressing appropriate signals to either promote or inhibit this process (Colello and Pott, Mol. Neurobiol. 15:83-100 (1997)).
CNS neurons have the inherent potential to regenerate after injury, but they are inhibited from doing so by inhibitory proteins present in myelin (Brittis et al., 2001, Neuron 30:11-14; Jones et al, 2002, J. Neurosci. 22:2792-2803; Grimpe et al, 2002, J. Neurosci.:22:3144-3160).
Several myelin inhibitory proteins found on oligodendrocytes have been characterized. Known examples of myelin inhibitory proteins include NogoA (Chen et al., Nature, 2000, 403, 434-439; Grandpre et al., Nature 2000, 403, 439-444), myelin associated glycoprotein (MAG) (McKerracher et al., 1994, Neuron 13:805-811; Mukhopadhyay et al., 1994, Neuron 13:757-767) and oligodendrocyte glycoprotein (OM-gp), Mikol et al., 1988, J. Cell. Biol. 106:1273-1279). Each of these proteins has been separately shown to be a ligand for the neuronal Nogo receptor-1 (NgR1) (Wang et al., Nature 2002, 417, 941-944; Grandpre et al., Nature 2000, 403, 439-444; Chen et al., Nature, 2000, 403, 434-439; Domeniconi et al., Neuron 2002, published online Jun. 28, 2002).
Recent studies of Nerve Growth Factor (NGF), and its receptor TrkA, suggest that different axonal signals control central and peripheral myelination. Indeed, as was previously reported, NGF has opposite effects on Schwann Cells (SC) and oligodendrocyte myelination (Chan et al., Neuron 43:183-91 (2004)).
Many diseases of the nervous system are associated with demyelination and dysmyelination, including multiple sclerosis (MS), progressive multi focal leukoencephalopathy (PML), encephalomyelitis (EPL), central pontine myelolysis (CPM), Wallerian Degeneration and some inherited diseases such as adrenoleukodystrophy, Alexander's disease, and Pelizaeus Merzbacher disease (PMZ). Among these diseases, MS is the most widespread, affecting approximately 2.5 million people worldwide.
MS generally begins with a relapsing-remitting pattern of neurological involvement, which then progresses to a chronic phase with increasing neurological damage. MS is associated with the destruction of myelin, oligodendrocytes and axons localized to chronic lesions. The demyelination observed in MS is not always permanent and remyelination has been documented in early stages of the disease. Remyelination of neurons requires oligodendrocytes.
Various disease-modifying treatments are available for MS, including the use of corticosteroids and immunomodulators such as interferon beta. In addition, because of the central role of oligodendrocytes and myelination in MS, there have been efforts to develop therapies to increase oligodendrocyte numbers or enhance myelination. See, e.g., Cohen et al., U.S. Pat. No. 5,574,009; Chang et al., N. Engl. J. Med. 346:165-73 (2002).
The use of Sp35 antagonists to promote myelination and oligodendrocyte and neuronal survival has been described, for example, in U.S. Published Application No. 2006/0009388 A1 and Mi et al., Nat. Neurosci. 7:221-228 (2004), both of which are herein incorporated by reference in their entireties. However, there remains an urgent need to devise additional therapies for MS.